Human interleukin-4 (IL-4) is a highly pleiotropic lymphokine which affects many different components of the immune system. It has T cell growth factor (TCGF) activity and B cell growth factor activity. It is capable of potentiating the TCGF activity of interleukin-2 (IL-2) and the colony forming activity of granulocyte-macrophage colony stimulating factor (GM-CSF). It also induces (a) the preferential production of IgG.sub.1 and IgE, (b) the low affinity receptor for IgE (CD23), and (c) the expression of human leukocyte class II DR antigens.
These activities suggest several possible therapeutic uses for IL-4, e.g., as an anti-tumor agent [Tepper et al., Cell 57:503 (1989)], a potentiating agent for IL-2 anticancer therapy, as a potentiating agent for GM-CSF-stimulated bone marrow regeneration, or as an agent to treat bare lymphocyte syndrome [Touraine, Lancet, pgs. 319-321 (Feb. 7, 1981); Touraine et at., Human Immunology 2:147 (1981); and Sullivan et at., J. Clin. Invest. 76:75 (1985)]. IL-4 and IL-4 agonists are thus potentially useful therapeutic agents.
On the other hand, the IgE- and CD23-inducing activity of IL-4 may have important adverse consequences for persons suffering from allergic diseases. The availability of IL-4 antagonists could provide an alternative to the use of glucocorticoid steroids, which have many deleterious side effects, especially with prolonged usage [Goodman and Gillman, The Pharmacological Basis of Therapeutics, 6th Ed. (MacMillan Publishing Company, New York, 1980)].
Monoclonal antibodies specific for blocking human IL-4 biological activity provide a means for constructing agonists or antagonists by generating anti-idiotype antibodies (U.S. Pat. No. 4,731,237) or by mimotope screening [Geysen et al., J. Immunol. Meth. 102:259 (1987); PCT patent applications WO 86/00991 and WO 86/06487]. Because most monoclonal antibodies are of rodent cell origin, however, there is a possibility that they would be immunogenic if used therapeutically in a human being, particularly over a long period of time.
To avoid this possibility, it is desirable to have human antibodies, or "humanized" antibodies, against human IL-4. The preparation of humanized antibodies against IL-4 has in fact been disclosed in International Patent Application Publication No. WO 93/17106. The disclosed antibodies while useful, however, do not have binding affinities equal to that of the starting rodent monoclonal antibody upon which they were based.
It would be desirable to have a humanized antibody against human IL-4 which would possess a binding affinity comparable to that of the rodent antibody. It cannot be predicted from the present state of the art, however, whether or how such an antibody could be produced.